G Protein Coupled Receptors: The Most Frequent Target of Pharmaceutical Agents

The G-protein-coupled receptor (GPCR), or 7-transmembrane (7-TM) receptor, superfamily is one of the largest groups of related genes in the entire genome with more than 300 members. Owing to the large number of physiological processes controlled by signaling through these receptors, the superfamily members make up the largest group of “druggable” targets in the body.

GPCR Family Groups

Sequence analysis of the genes contained within the human genome has identified large numbers of GPCR genes (>300) and remarkably enough the function of a sizable portion remain unknown. But based on sequence similarities, the GPCRs have been divided into 6 different classes. All of the members of this group of proteins have seven transmembrane spanning segments. The biochemical and pharmacologic characterization of the original members of the superfamily identified them as utilizing small GTP binding proteins to transduce their intracellular signal once activated.

Examples of GPCR Proteins and Their Functions

GPCRs are involved in many different cellular processes. One of the best characterized members is the light-transducing protein known as rhodopsin. This protein and several close relatives are responsible for the specialized pigment present in the rods and cones of the retina that allow for sensing of light, and the sense of vision. The receptors in cells that respond to the hormone adrenaline, the adrenoreceptors, are GPCRs. Many important neurotransmitter receptors are members of the GPCR superfamily including receptors for serotonin and for glutamate. One of the most widely known by the public at large, and seasonally appreciated members of the GPCR superfamily are the histamine receptors. The sense of smell is possible because of GPCRs that detect odor molecules.

Common Drugs That Target GPCRs

Because of the widespread distribution of GPCRs throughout the body, their presence on the surface of cells and the vast array of cellular processes that they can modulate, GPCRs are the target of more drugs than any other targeted protein in the body. Name a body response and a need to control it and there is likely a GPCR involved and a drug available to modulate it.

  • Stomach Acid Relief: Histamine H2 Receptor blockers like Zantac and Tagamet
  • Allergy or Hayfever Relief: Histamine H1 Receptor blockers like Benadryl and Claritin
  • Blood Pressure or Heart Rate Control: beta-Adrenoceptor blockers like sotalol, timolol, atenolol, propranolol, and many, many others
  • Motion Sickness: Muscarinic Acetylcholine Receptor blocker scopolamine
  • Dilated Eye Examination: Muscarinic Acetylcholine Receptor blocker tropicamide
  • Severe Psychiatric Disorder: Dopamine Receptor blocker haloperidol

The list of potential GPCR targets and the drugs that have been developed to affect their function is extremely long. And as the functions of the 100 or so other GPCRs with as yet unknown physiological effects are identified, the list of drugs that target GPCRs will grow ever longer.

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